Long non‑coding RNA plasmacytoma variant translocation 1 gene promotes the development of cervical cancer via the NF‑κB pathway

  • Authors:
    • Chang Wang
    • Hao Zou
    • Hongjuan Yang
    • Lei Wang
    • Huijun Chu
    • Jinwen Jiao
    • Yankui Wang
    • Aiping Chen
  • View Affiliations

  • Published online on: July 9, 2019     https://doi.org/10.3892/mmr.2019.10479
  • Pages: 2433-2440
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The long noncoding RNA plasmacytoma variant translocation 1 gene (LncRNA PVT1) has an important role in tumor occurrence and development, yet the role and underlying molecular mechanisms of this RNA in cervical cancer have not yet been elucidated. In the present study, three cervical cancer cell lines (HeLa, Ca Ski and SiHa) were used to verify how LncRNA PVT1 mediates cervical cancer development, and the H8 cell line was used as a control. A LncRNA PVT1 overexpression vector or small interfering RNAs targeting LncRNA PVT1 were transfected into cervical cancer cells to generate LncRNA PVT1 overexpression and silencing in these cells. LncRNA PVT1 overexpression accelerated the growth of cervical cancer cells by advancing the cell cycle and inhibiting cellular apoptosis; increases in Cyclin D1 (CCND1) mRNA and activated Bcl‑2 protein expression levels also supported this finding. Furthermore, NF‑κB activation and expression was increased by LncRNA PVT1 overexpression. In addition, NF‑κB activation or inhibition induced changes in cell viability, accompanied by changes in CCND1 and Bcl‑2 expression. Increases or decreases in microRNA‑16 (miR‑16) expression (using miR mimics and inhibitors) also corresponded to changes in LncRNA PVT1 expression, in vitro. miR‑16 mimics and inhibitor had opposite effects to those of NF‑κB activity, and miR‑16 was demonstrated to directly interact with the NF‑κB gene as measured using the dual‑luciferase assay. In summary, LncRNA PVT1 inhibits the effect of miR‑16, promoting the cell cycle and inhibiting cellular apoptosis of cervical cancer cells, potentially via the NF‑κB pathway. The data from the present study will contribute to the current knowledge surrounding the theoretical basis of cervical cancer and provide a new perspective for the treatment of cervical cancer.

References

1 

Joo YH, Jung CK, Sun DI, Park JO, Cho KJ and Kim MS: High-risk human papillomavirus and cervical lymph node metastasis in patients with oropharyngeal cancer. Head Neck. 34:10–14. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

3 

den Boon JA, Pyeon D, Wang SS, Horswill M, Schiffman M, Sherman M, Zuna RE, Wang Z, Hewitt SM, Pearson R, et al: Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. Proc Natl Acad Sci USA. 112:E3255–E3264. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Dalstein V, Riethmuller D, Prétet JL, Le Bail Carval K, Sautière JL, Carbillet JP, Kantelip B, Schaal JP and Mougin C: Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: A longitudinal French cohort study. Int J Cancer. 106:396–403. 2003. View Article : Google Scholar : PubMed/NCBI

5 

Nees M, Geoghegan JM, Hyman T, Frank S, Miller L and Woodworth CD: Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kappaB-responsive genes in cervical keratinocytes. J Virol. 75:4283–4296. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Spitkovsky D, Hehner SP, Hofmann TG, Möller A and Schmitz ML: The human papillomavirus oncoprotein E7 attenuates NF-kappa B activation by targeting the Ikappa B kinase complex. J Biol Chem. 277:25576–25582. 2002. View Article : Google Scholar : PubMed/NCBI

7 

James MA, Lee JH and Klingelhutz AJ: Human papillomavirus type 16 E6 activates NF-kappaB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J Virol. 80:5301–5307. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Jia QP, Yan CY, Zheng XR, Pan X, Cao X and Cao L: Upregulation of MTA1 expression by human papillomavirus infection promotes CDDP resistance in cervical cancer cells via modulation of NF-κB/APOBEC3B cascade. Cancer Chemother Pharmacol. 83:625–637. 2019. View Article : Google Scholar : PubMed/NCBI

9 

Gilmore TD: Introduction to NF-kappaB: Players, pathways, perspectives. Oncogene. 25:6680–6684. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Jiang N, Xie F, Guo Q, Li MQ, Xiao J and Sui L: Toll-like receptor 4 promotes proliferation and apoptosis resistance in human papillomavirus-related cervical cancer cells through the Toll-like receptor 4/nuclear factor-κB pathway. Tumour Biol. 39:10104283177105862017. View Article : Google Scholar : PubMed/NCBI

11 

Perkins ND: The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer. 12:121–132. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS and Reed JC: IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17:2215–2223. 1998. View Article : Google Scholar : PubMed/NCBI

13 

Ono H, Iizumi Y, Goi W, Sowa Y, Taguchi T and Sakai T: Ribosomal protein S3 regulates XIAP expression independently of the NF-κB pathway in breast cancer cells. Oncol Rep. 38:3205–3210. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Chen QM and Tu VC: Apoptosis and heart failure: Mechanisms and therapeutic implications. Am J Cardiovasc Drugs. 2:43–57. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Prusty BK, Husain SA and Das BC: Constitutive activation of nuclear factor-kB: Preferntial homodimerization of p50 subunits in cervical carcinoma. Front Biosci. 10:1510–1519. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Pardini B, De Maria D, Francavilla A, Di Gaetano C, Ronco G and Naccarati A: MicroRNAs as markers of progression in cervical cancer: A systematic review. BMC Cancer. 18:6962018. View Article : Google Scholar : PubMed/NCBI

17 

Liu J, Yang L, Zhang J, Zhang J, Chen Y, Li K, Li Y, Li Y, Yao L and Guo G: Knock-down of NDRG2 sensitizes cervical cancer Hela cells to cisplatin through suppressing Bcl-2 expression. BMC Cancer. 12:3702012. View Article : Google Scholar : PubMed/NCBI

18 

Zubillaga-Guerrero MI, Alarcón-Romero Ldel C, Illades-Aguiar B, Flores-Alfaro E, Bermúdez-Morales VH, Deas J and Peralta-Zaragoza O: MicroRNA miR-16-1 regulates CCNE1 (cyclin E1) gene expression in human cervical cancercells. Int J Clin Exp Med. 8:15999–16006. 2015.PubMed/NCBI

19 

Liu Z, Wu M, Shi H, Huang C, Luo S and Song X: DDN-AS1-miR-15a/16-TCF3 feedback loop regulates tumor progression in cervical cancer. J Cell Biochem. 120:10228–10238. 2018. View Article : Google Scholar : PubMed/NCBI

20 

Huang Y, Chen G, Wang Y, He R, Du J, Jiao X and Tai Q: Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-κB signaling pathway in hepatocellular carcinoma. Biochem Biophys Res Commun. 503:1035–1041. 2018. View Article : Google Scholar : PubMed/NCBI

21 

Yang TQ, Lu XJ, Wu TF, Ding DD, Zhao ZH, Chen GL, Xie XS, Li B, Wei YX, Guo LC, et al: MicroRNA-16 inhibits glioma cell growth and invasion through suppression of BCL2 and the nuclear factor-κB1/MMP9 signaling pathway. Cancer Sci. 105:265–271. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Qi F, Liu X, Wu H, Yu X, Wei C, Huang X, Ji G, Nie F and Wang K: Long noncoding AGAP2-AS1 is activated by SP1 and promotes cell proliferation and invasion in gastric cancer. J Hematol Oncol. 10:482017. View Article : Google Scholar : PubMed/NCBI

23 

Bai Y, Dai X, Harrison AP and Chen M: RNA regulatory networks in animals and plants: A long noncoding RNA perspective. Brief Funct Genomics. 14:91–101. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Chen LL and Carmichael GG: Decoding the function of nuclear long non-coding RNAs. Curr Opin Cell Biol. 22:357–364. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Wierzbicki AT: The role of long non-coding RNA in transcriptional gene silencing. Curr Opin Plant Biol. 15:517–522. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Ben Amor B, Wirth S, Merchan F, Laporte P, d'Aubenton- Carafa Y, Hirsch J, Maizel A, Mallory A, Lucas A, Deragon JM, et al: Novel long nonprotein coding RNAs involved in Arabidopsis differentiation and stress responses. Genome Res. 19:57–69. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Ma X, Shao C, Jin Y, Wang H and Meng Y: Long non-coding RNAs: A novel endogenous source for the generation of dicer-like 1-dependent small RNAs in Arabidopsis thaliana. RNA Biol. 11:373–390. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Salmena L, Poliseno L, Tay Y, Kats L and Pandolfi PP: A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language. Cell. 146:353–358. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Karreth FA, Tay Y, Perna D, Ala U, Tan SM, Rust AG, DeNicola G, Webster KA, Weiss D, Perez-Mancera PA, et al: In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell. 147:382–395. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Tay Y, Kats L, Salmena L, Weiss D, Tan SM, Ala U, Karreth F, Poliseno L, Provero P, Di Cunto F, et al: Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell. 147:344–357. 2011. View Article : Google Scholar : PubMed/NCBI

31 

Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A and Bozzoni I: A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 147:358–369. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Wang C, Han C, Zhang Y and Liu F: LncRNA PVT1 regulate expression of HIF1α via functioning as ceRNA for miR-199a-5p in non-small cell lung cancer under hypoxia. Mol Med Rep. 17:1105–1110. 2018.PubMed/NCBI

33 

Guo D, Wang Y, Ren K and Han X: Knockdown of LncRNA PVT1 inhibits tumorigenesis in non-small-cell lung cancer by regulating miR-497 expression. Exp Cell Res. 362:172–179. 2018. View Article : Google Scholar : PubMed/NCBI

34 

Yang JP, Yang XJ, Xiao L and Wang Y: Long noncoding RNA PVT1 as a novel serum biomarker for detection of cervical cancer. Eur Rev Med Pharmacol Sci. 20:3980–3986. 2016.PubMed/NCBI

35 

Iden M, Fye S, Li K, Chowdhury T, Ramchandran R and Rader JS: The lncRNA PVT1 Contributes to the cervical cancer phenotype and associates with poor patient prognosis. PLoS One. 11:e01562742016. View Article : Google Scholar : PubMed/NCBI

36 

Shen CJ, Cheng YM and Wang CL: LncRNA PVT1 epigenetically silences miR-195 and modulates EMT and chemoresistance in cervical cancer cells. J Drug Target. 25:637–644. 2017. View Article : Google Scholar : PubMed/NCBI

37 

Wang X, Wang G, Zhang L, Cong J, Hou J and Liu C: LncRNA PVT1 promotes the growth of HPV positive and negative cervical squamous cell carcinoma by inhibiting TGF-β1. Cancer Cell Int. 18:702018. View Article : Google Scholar : PubMed/NCBI

38 

Zhang S, Zhang G and Liu J: Long noncoding RNA PVT1 promotes cervical cancer progression through epigenetically silencing miR-200b. APMIS. 124:649–658. 2016. View Article : Google Scholar : PubMed/NCBI

39 

Gao YL, Zhao ZS, Zhang MY, Han LJ, Dong YJ and Xu B: Long Noncoding RNA PVT1 facilitates cervical cancer progression via negative regulating of miR-424. Oncol Res. 25:1391–1398. 2017. View Article : Google Scholar : PubMed/NCBI

40 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

41 

Wang F, Yang L, Sun J, Zheng J, Shi L, Zhang G and Cui N: Tumor suppressors microRNA-302d and microRNA-16 inhibit human glioblastoma multiforme by targeting NF-κB and FGF2. Mol Biosyst. 13:1345–1354. 2017. View Article : Google Scholar : PubMed/NCBI

42 

Wong L, Power N, Miles A and Tropepe V: Mutual antagonism of the paired-type homeobox genes, vsx2 and dmbx1, regulates retinal progenitor cell cycle exit upstream of ccnd1 expression. Dev Biol. 402:216–228. 2015. View Article : Google Scholar : PubMed/NCBI

43 

Valentin R, Grabow S and Davids MS: The rise of apoptosis: Targeting apoptosis in hematologic malignancies. Blood. 132:1248–1264. 2018. View Article : Google Scholar : PubMed/NCBI

44 

Hsieh SC, Hsieh WJ, Chiang AN, Su NW, Yeh YT and Liao YC: The methanol-ethyl acetate partitioned fraction from Chinese olive fruits inhibits cancer cell proliferation and tumor growth by promoting apoptosis through the suppression of the NF-κB signaling pathway. Food Funct. 7:4797–4803. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Xie S, Liu B, Fu S, Wang W, Yin Y, Li N, Chen W, Liu J and Liu D: GLP-2 suppresses LPS-induced inflammation in macrophages by inhibiting ERK phosphorylation and NF-κB activation. Cell Physiol Biochem. 34:590–602. 2014. View Article : Google Scholar : PubMed/NCBI

46 

Reid G, Pel ME, Kirschner MB, Cheng YY, Mugridge N, Weiss J, Williams M, Wright C, Edelman JJ, Vallely MP, et al: Restoring expression of miR-16: A novel approach to therapy for malignant pleural mesothelioma. Ann Oncol. 24:3128–3135. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2019
Volume 20 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, C., Zou, H., Yang, H., Wang, L., Chu, H., Jiao, J. ... Chen, A. (2019). Long non‑coding RNA plasmacytoma variant translocation 1 gene promotes the development of cervical cancer via the NF‑κB pathway. Molecular Medicine Reports, 20, 2433-2440. https://doi.org/10.3892/mmr.2019.10479
MLA
Wang, C., Zou, H., Yang, H., Wang, L., Chu, H., Jiao, J., Wang, Y., Chen, A."Long non‑coding RNA plasmacytoma variant translocation 1 gene promotes the development of cervical cancer via the NF‑κB pathway". Molecular Medicine Reports 20.3 (2019): 2433-2440.
Chicago
Wang, C., Zou, H., Yang, H., Wang, L., Chu, H., Jiao, J., Wang, Y., Chen, A."Long non‑coding RNA plasmacytoma variant translocation 1 gene promotes the development of cervical cancer via the NF‑κB pathway". Molecular Medicine Reports 20, no. 3 (2019): 2433-2440. https://doi.org/10.3892/mmr.2019.10479